IP Library › Granted Patent US 12,331,076
Granted Patent B2
US 12,331,076 · App. 16/595,980 · Granted Jun 17, 2025

Alphavirus-based replicons for administration of biotherapeutics

Inventors: Jason L. Dehart (San Diego, CA); Nathaniel Stephen Wang (San Diego, CA); Parinaz Aliahmad (San Diego, CA); Shigeki Miyake-Stoner (La Jolla, CA); Kurt Iver Kamrud (Olathe, KS)
Assignee: Janssen Pharmaceuticals, Inc.
C07K14/005C12N7/00A61K38/00C12N2770/36122C12N2770/36133C12N2770/36143
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Quick Facts
Patent No.
US 12,331,076
App. No.
16/595,980
Granted
Jun 17, 2025
Kind
B2
Abstract

The invention provides RNA replicons useful for administering a heterologous protein or peptide into a mammal and eliciting a reduced immune response or no immune response from the mammal. The RNA replicons have RNA sequences encoding for a heterologous protein or peptide, New World alphavirus nonstructural proteins nsP1, nsP2, and nsP4; and an alphavirus nsP3 protein macro domain, central domain, and hypervariable domain. The encoded hypervariable domain can have an amino acid sequence derived from an Old World alphavirus nsP3 hypervariable domain; or can have an amino acid sequence derived from a portion of a New World alphavirus nsP3 hypervariable domain, and another portion derived from an Old World alphavirus nsP3 hypervariable domain.

Claims (56)

1. An RNA replicon comprising

(i) an RNA sequence encoding a heterologous protein or peptide;

(ii) 5′ and 3′ alphavirus untranslated regions;

(iii) RNA sequences encoding amino acid sequences derived from New World alphavirus nonstructural proteins nsP1, nsP2, and nsP4; and

(iv) an RNA sequence encoding a nonstructural nsP3, wherein said nsP3 comprises (a) an amino acid sequence derived from an alphavirus nsP3 macro domain;

(b) an RNA sequence encoding an amino acid sequence derived from an alphavirus nsP3 central domain; and

(c) an RNA sequence encoding an amino acid sequence derived from an alphavirus nsP3 hypervariable domain (HVD) comprising at least a portion of an Old World alphavirus nsP3 HVD comprising a FGDF (SEQ ID NO: 18) or a FGSF (SEQ ID NO: 19) motif, wherein said alphavirus nsP3HVD comprises:

an amino acid sequence derived from an Old World alphavirus nsP3 HVD comprising said portion of the Old World alphavirus nsP3 HVD; or

an amino acid sequence comprising a portion derived from a New World alphavirus nsP3 HVD, and said portion derived from the Old World alphavirus nsP3 HVD; and wherein the replicon does not encode at least protein C.

2. The RNA replicon of claim 1 , wherein the Old World alphavirus is selected from the group consisting of: Sindbis virus (SINV), Chickungunya virus (CHIKV), Semliki Forest Virus (SFV), Ross River Virus (RRV), Sagiyama virus (SAGV), Getah virus (GETV), Middleburg virus (MIDV), Bebaru (BEBV), O'nyong nyong virus (ONNV), Ndumu (NDUV), and Barmah Forest virus (BFV).

3. The RNA replicon of claim 2 , wherein the Old World alphavirus is selected from the group consisting of: CHIKV, SINV, and SFV.

4. The RNA replicon of claim 1 , wherein the New World alphavirus is selected from the group consisting of: a Venezuelan equine encephalitis virus (VEEV), a western equine encephalitis virus (WEEV), and an eastern equine encephalitis virus (EEEV).

5. The RNA replicon of claim 1 , wherein the portion derived from the Old World alphavirus nsP3 HVD comprises a repeat selected from the group consisting of: an FGDF/FGDF (SEQ ID NO: 20) repeat, an FGSF/FGSF (SEQ ID NO: 21) repeat, an FGDF/FGSF (SEQ ID NO: 22) repeat, and an FGSF/FGDF (SEQ ID NO: 23) repeat; and further wherein the repeat sequences are separated by at least 10 but not more than 25 amino acids.

6. The RNA replicon of claim 5 , wherein the repeat sequence is separated by an amino acid sequence selected from the group consisting of: NEGEIESLSSELLT (SEQ ID NO: 6), SDGEIDELSRRVTTESEPVL (SEQ ID NO: 7), or DEHEVDALASGIT (SEQ ID NO: 8).

7. The RNA replicon of claim 1 , wherein the alphavirus nsP3 HVD comprises a portion derived from the Old World alphavirus nsP3 HVD having:

a. amino acids 479-482 or 497-500 or 479-500 or 335-517 of CHIKV nsP3 HVD;

b. amino acids 451-454 or 468-471 or 451-471 of SFV nsP3 HVD; or

c. amino acids 490-493 or 513-516 or 490-516 or 335-538 of SINV nsP3 HVD.

8. The RNA replicon of claim 7 , wherein the portion derived from the Old World alphavirus nsP3 HVD comprises amino acids 335-517 of CHIKV nsP3 HVD or amino acids 335-538 of SINV HVD.

9. The RNA replicon of claim 1 , wherein the alphavirus nsP3 HVD comprises a portion derived from:

a. the New World alphavirus VEEV nsP3 HVD, but does not comprise amino acids 478-518 of the VEEV nsP3 HVD;

b. the New World alphavirus VEEV nsP3 HVD, but does not comprise amino acids 478-545 of the VEEV nsP3 HVD;

c. the New World alphavirus VEEV nsP3 HVD, but does not comprise amino acids 335-518 of the VEEV nsP3 HVD;

d. the New World alphavirus VEEV nsP3 HVD, but does not comprise amino acids 335-538 of the VEEV nsP3 HVD;

e. the New World alphavirus EEEV nsP3 HVD, but does not comprise amino acids 531-547 of the EEEV nsP3 HVD; or

f. the New World alphavirus WEEV nsP3 HVD, but does not comprise amino acids 504-520 of the WEEV nsP3 HVD.

10. The RNA replicon of claim 9 , wherein

a. the New World alphavirus is EEEV, and the alphavirus nsP3 HVD comprises a portion derived from the New World alphavirus nsP3 HVD not comprising amino acids 531-547 of the EEEV nsP3 HVD, and comprises a portion derived from the Old World alphavirus nsP3 HVD comprising amino acids 479-500 of CHIKV nsP3 HVD, amino acids 451-471 of SFV nsP3 HVD, or amino acids 490-516 of SINV nsP3 HVD;

b. the New World alphavirus is WEEV, and the alphavirus nsP3 HVD comprises a portion derived from the New World alphavirus nsP3 HVD not comprising amino acids 504-520 of the WEEV nsP3 HVD, and comprises a portion derived from the Old World alphavirus nsP3 HVD comprising amino acids 479-500 of CHIKV nsP3 HVD, amino acids 451-471 of SFV nsP3 HVD, or amino acids 490-516 of SINV nsP3 HVD; or

c. the New World alphavirus is VEEV, and the alphavirus nsP3 HVD comprises a portion derived from the New World alphavirus nsP3 HVD not comprising amino acids 335-518 of the VEEV nsP3 HVD, and comprises a portion derived from the Old World alphavirus nsP3 HVD comprising amino acids 490-493, 513-516, 490-516, or 335-538 of SINV nsP3 HVD.

11. The RNA replicon of claim 1 , further comprising a sub-genomic promoter that is operably linked to and regulates translation of the RNA sequence encoding the heterologous protein.

12. The RNA replicon of claim 1 , further comprising a 5′ cap and a 3′ poly-A tail.

13. The RNA replicon of claim 1 , wherein the replicon comprises positive sense, single-stranded RNA.

14. The RNA replicon of claim 1 , wherein the replicon comprises 9-11 kb of RNA and has a diameter of 30-50 nm.

15. The RNA replicon of claim 1 , wherein the heterologous protein is

a. a biotherapeutic protein or peptide; or

b. an antibody.

16. An RNA replicon comprising

(i) an RNA sequence encoding a heterologous protein or peptide;

(ii) RNA sequences encoding amino acid sequences derived from New World alphavirus nonstructural proteins nsP1, nsP2, and nsP4; and

(iii) an RNA sequence encoding an amino acid sequence derived from an Old World alphavirus nsP3 protein, wherein the first 1-6 amino acids on the N-terminal and/or C-terminal side of the nsP3 protein are derived from a New World alphavirus sequence;

wherein the replicon does not encode at least protein C.

17. A method of administering a heterologous protein or peptide to a mammal comprising administering to the mammal a pharmaceutical composition comprising the RNA replicon of claim 1 , wherein the heterologous protein or peptide is expressed within the mammal.

18. An alphavirus replicon RNA, comprising: in order from 5′ to 3′ end,

(i) an alphavirus 5′ untranslated sequence for directing replication of the alphavirus replicon;

(ii) an RNA sequence encoding alphaviral nonstructural proteins nsP1, nsP2, nsP3, and nsP4;

(iii) an alphavirus subgenomic promoter sequence;

(iv) an RNA sequence encoding one or more heterologous proteins or peptides; and

(v) an alphavirus 3′ untranslated sequence;

wherein the nsP1, nsP2 and nsP4 are from one or more New World alphaviruses, wherein the nsP3 comprises, in order from amino-terminus to carboxyl terminus: an alphavirus nsP3 macro domain, an alphavirus nsP3 central domain, and an alphavirus nsP3 hypervariable domain (HVD),

wherein the macro domain and the central domain are from one or more New World alphaviruses and/or Old World alphaviruses,

wherein the HVD comprises at least a portion of an Old World alphavirus HVD comprising a repeat selected from the group consisting of: an FGDF/FGDF (SEQ ID NO: 20) repeat, an FGSF/FGSF (SEQ ID NO: 21) repeat, an FGDF/FGSF (SEQ ID NO: 22) repeat, and an FGSF/FGDF (SEQ ID NO: 23) repeat; and further wherein the repeat sequences are separated by at least 10 but not more than 25 amino acids; wherein the HVD comprises the Old World alphavirus HVD comprising said portion of the Old World alphavirus HVD, or the HVD comprises a portion of an HVD from a New World alphavirus and said portion of an HVD from the Old World alphavirus;

wherein the New World alphavirus is selected from the group consisting of: a Venezuelan equine encephalitis virus (VEEV), a western equine encephalitis virus (WEEV), and an eastern equine encephalitis virus (EEEV); and the Old World alphavirus is selected from the group consisting of: Sindbis virus (SINV), Chickungunya virus (CHIKV), Semliki Forest Virus (SFV), Ross River Virus (RRV), Sagiyama virus (SAGV), Getah virus (GETV), Middleburg virus (MIDV), Bebaru virus (BEBV), O'nyong nyong virus (ONNV), Ndumu (NDUV), and Barmah Forest virus (BFV); and

wherein the replicon does not encode at least protein C.

19. The alphavirus replicon RNA of claim 18 , wherein the nsP1, nsP2, nsP4, nsP3 macro domain, and nsP3 central domain are from VEEV, and the nsP3 HVD comprises a portion of an HVD from VEEV and a portion of an HVD from an Old World alphavirus selected from the group consisting of SINV, CHIKV and SFV.

20. The RNA replicon of claim 19 , wherein the heterologous protein is a biotherapeutic protein or peptide.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 5, 2019
From: DEHART, JASON L.; WANG, NATHANIEL STEPHEN; ALIAHMAD, PARINAZ; MIYAKE-STONER, SHIGEKI; KAMRUD, KURT IVER
To: JANSSEN PHARMACEUTICALS, INC.
Reel/Frame 050916/0648 →
Continuity (2)
Provisional Application 62742868 · Oct 8, 2018
Related Publication 20200109178A1 · Apr 9, 2020
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